Paneth cells directly sense gut commensals and maintain homeostasis at the intestinal host-microbial interface

Abstract

The intestinal epithelium is in direct contact with a vast microbiota, yet little is known about how epithelial cells defend the host against the heavy bacterial load. To address this question we studied Paneth cells, a key small intestinal epithelial lineage. We found that Paneth cells directly sense enteric bacteria through cell-autonomous MyD88-dependent toll-like receptor (TLR) activation, triggering expression of multiple antimicrobial factors. Paneth cells were essential for controlling intestinal barrier penetration by commensal and pathogenic bacteria. Furthermore, Paneth cell-intrinsic MyD88 signaling limited bacterial penetration of host tissues, revealing a role for epithelial MyD88 in maintaining intestinal homeostasis. Our findings establish that gut epithelia actively sense enteric bacteria and play an essential role in maintaining host-microbial homeostasis at the mucosal interface.commensal bacteria ͉ epithelium ͉ innate immunity ͉ intestine ͉ toll-like receptors H umans harbor nearly 100 trillion intestinal bacteria that are essential for health. Millions of years of coevolution have molded this human-microbe interaction into a symbiotic relationship in which gut bacteria make essential contributions to human nutrient metabolism and in return occupy a nutrient-rich environment (1). However, bacterial invasion of tissue can result in breakdown of this symbiotic association and lead to pathologies such as inflammatory bowel disease (2). Intestinal epithelia constitute the major interface between the microbiota and internal host tissues. Despite the enormous numbers of commensal bacteria, microbial incursions across mucosal surfaces are relatively rare, suggesting that intestinal epithelia harbor highly effective mechanisms for controlling microbial interactions with the host mucosal interface. However, little is known about how intestinal epithelial cells maintain homeostasis with vast, complex populations of enteric bacteria.The Paneth cell is a specialized small intestinal epithelial lineage that resides at the base of crypts of Lieberkühn and contributes to intestinal innate immunity by secreting a diverse repertoire of antimicrobial proteins (3). Several antimicrobial factors in Paneth cells are expressed under the control of indigenous microorganisms (4, 5). In addition, ex vivo studies on isolated small intestinal crypts indicate that secretion of antimicrobial products is triggered by bacterial signals (3). However, itis not yet clear whether Paneth cells detect bacteria through cell-autonomous mechanisms. Furthermore, although Paneth cells are known to secrete abundant antimicrobial factors (3), the in vivo functional role of Paneth cells in maintaining homeostasis with commensal bacterial populations has not been established.In this report, we show that Paneth cells detect enteric bacteria through cell-autonomous MyD88 activation, triggering expression of multiple antimicrobial factors. We show that Paneth cell-intrinsic MyD88 signaling limits bacterial penetration of host tissues, disclo...

Starvation Compromises Paneth Cells

“…25 Second, they are crucial in smallintestinal immunity by sensing and responding to enteric bacteria, protecting stem cells and limiting penetration of the intestinal wall by both commensal and pathogenic bacteria. 3 To this end, Paneth cells produce and secrete cytoplasmic granules containing a battery of antimicrobial proteins. 26 Because enteral starvation and the use of total parenteral nutrition result in bacterial translocation in critically ill patients, 10 we hypothesized that the absence of oral food intake compromises Paneth cell functionality and its role in gut protection.…”

“…2 Using a murine cell ablation model, Paneth cells were shown to be crucial in host protection against invasion of both commensal and pathogenic microbiota. 3 In addition, our group has recently shown the additive importance of Paneth cells in preventing bacterial translocation in situations of physical intestinal barrier loss. 4 Enteral starvation and total parenteral nutrition, as applied to critically ill patients, are reported to result in increased gut wall permeability, a compromised immune system, and bacterial translocation.…”

Nutrition, intestinal defence and the microbiome

“…Furthermore, the composition of the flora is altered (69) and it is tempting to speculate that this outcome may be an important role of intestinal antimicrobial peptide expression, as it has been established that such expression responds to the microbiota (23) .…”

Paneth cells: the hub for sensing and regulating intestinal flora

“…AMPs from Paneth cells are essential for controlling intestinal Listeria monocytogenes infection (Kaser et al, 2008;Kobayashi et al, 2005). Depleting Paneth cells in mice results in a compromised intestinal barrier and enhanced translocation and dissemination of pathogens (Vaishnava et al, 2008).…”